The immune system is a complicated network of cells and cell components (molecules) that normally work to defend the body and eliminate infections caused by bacteria, viruses, and other invading foreign bodies. If a person has an autoimmune disease, the immune system mistakenly attacks self, targeting the cells, tissues and organs of a person's own body. A collection of immune system cells and molecules at a target site may be broadly referred to as inflammation.
There are many different autoimmune diseases, and they can each affect the body in different ways. Many of the autoimmune diseases are rare. As a group, however, autoimmune diseases afflict millions of people.
Some autoimmune diseases are known to begin or worsen with certain triggers such as viral, parasitic and chronic bacterial infections. Other less understood influences affect the immune system and the course of autoimmune diseases include ageing, chronic stress, hormones and pregnancy.
Autoimmune diseases are often chronic, requiring lifelong care and monitoring, even when the person may look or feel well. Currently, few autoimmune diseases can be cured or made to go into remission with treatment.
Physicians most often help patients manage the consequences of inflammation caused by the autoimmune disease. In some people, a limited number of immuno-suppressive medications may result in disease remission. However, even if their disease goes into remission, patients are rarely able to discontinue medication. The long-term side effects of immunosuppressive medication can be substantial.
Initiation and progression of vascular injury is a complex, multi-factorial process, but there is growing evidence that inflammatory responses play a key role. Vascular injury is involved in the development of atherosclerosis, and in thrombotic processes that lead to acute ischaemic syndromes such as myocardial infarction, stroke and peripheral artery occlusion.
Immune mechanisms may be important in the development and maintenance of atherosclerosis and myointimal hyperplasia (MIH).
Myointimal Hyperplasia (MIH) can be considered as an exaggerated healing response to injury such as balloon angioplasty. A cascade of events results in: loss of the basement membrane, migration of vascular smooth muscle cells (VSMC) from the media into the intima, VSMC proliferation and phenotypic change to a more secretory fibroblastic cell type and increased production of extracellular matrix, which eventually leads to stenosis or occlusion of the vessel. It occurs after bypass grafting and balloon angioplasty and affects approximately 30% of such cases in clinical practice. It is the major cause of failure of such procedures and treatment of the resulting stenosed and blocked vessels/grafts is problematic. The underlying cellular mechanisms leading to MIH are not well understood and to date no therapy had been developed which can effectively prevent it. The clinical relevance of the current patent relates to the very large numbers of coronary artery angioplasties which are performed annually in the UK and world-wide. Although drug eluting stents are currently producing promising results they are unlikely to prevent restenosis completely. Any safe, relatively inexpensive adjunctive therapy, such as the immunotherapy proposed in this patent, would have a major clinical impact.
The mechanisms involved in immunotherapy against restenosis are complex and not completely elucidated The endothelial injury caused by angioplasty may be exacerbated by the host immune response to hsp's. Hsp's are proteins produced by stressed cells which have been implicated in the pathogenesis and the pathophysiology of various immunological disorders including atherosclerosis (Xu Q et al. Arterioscler Thromb 1992; 12: 789-799). It is likely that they will be present on endothelial and smooth muscle cells in the region of an angioplasty. In effect the hsp acts as an autoantigen which can then be attacked by the immune system. This situation can be induced experimentally by immunizing with a cross-reactive mycobacterial hsp (hsp65) which leads to endothelial damage in rabbits and mice (Xu Q, et al. Arterioscler Thromb 1992; 12: 789-799 and George J, et al. Circ. Res. 2000; 86: 1203-1210). The effect appears to be dependent on IL-4 secreted by Th2 lymphocytes, and is probably mediated by antibody (George J, et al. Circ. Res. 2000; 86: 1203-1210 and Schett G, et al. J. Clin. Invest. 1995; 96: 2569-2577). The relevance of these observations to man is suggested by the ability of affinity-purified human antibody eluted from hsp65 columns to damage stressed human endothelial cells in vitro. This finding suggests that the antibody cross-reacts with hsp60 which is the human homologue of hsp65, and may be accessible to antibody when expressed on the membranes of stressed endothelial cells. It has been suggested that such antibodies binding to stressed endothelial cells may be a factor in producing coronary artery disease after heart transplantation (Crisp S J et al. J Heart Lung Transplant 1994; 81-91). Mukherjee et al (Thromb Haemost 1996; 75: 258-60) showed no association between preoperative antibody levels to hsp65 and coronary restenosis, but did show that those patients where levels of such antibodies dropped after angioplasty were less likely to restenose. In fact the role of antibodies to hsp could be complex, because patients with vascular disease have not only raised antibody, but also raised levels of the hsp themselves (Wright B H, et al Heart Vessels 2000; 15: 18-22). Thus an apparent fall in antibody levels may merely reflect an increase in levels of the protein. Moreover the hsp have regulatory effects, and bind to arterial smooth muscle cells, leading to enhanced survival without a requirement for internalization (Johnson A D et al. Atherosclerosis 1990; 84: 111-119).